ABSTRACT Recent large-scale whole exome sequencing studies have identified protein function-altering variants occurring at low allele frequency in populations, for which the health impact is unknown. Our ongoing investigation of exonic variation in American Indians using whole exome sequencing has uncovered single nucleotide variants and small indels with predicted protein-altering function, which were genotyped in 1,127 Strong Heart Family Study participants. The main goal of this application is to assess the clinical and biological consequences of these variants for phenotypes relevant to heart and blood diseases. We will use the existing comprehensive phenotypic data on clinical assessments and biomarkers obtained in two clinical visits and the surveillance data on cardiovascular disease events to perform phenome-wide association analyses. The family data will allow mapping individuals with these variants in pedigrees to better understand their phenotypic correlations. This proposal addresses important gaps in our knowledge of the clinical phenotypes associated with rare protein function-altering variants in humans, which may have implications for precision medicine.